The work in this laboratory is focused on clinical studies of the relationships between bile acid metabolism and cholesterol gallstone formation. Our goal is to define precisely how changes in hepatic synthesis, ileal absorption, fecal excretion and pool sizes of bile acids influence the compostion of biliary lipids and the solubility of biliary cholesterol. The abnormalities in bile acid and cholesterol metabolism existing in patients with cholelithiasis or ileal dysfunction, and the changes in biliary lipids induced by oral contraceptives or by treatment of hyperlipidemic subjects with clofibrate comprise the nucleus of this project. Studies of the effects of cholecystectomy on the composition of biliary lipids, in the steady state, will enhance our understanding of the role of the liver in cholesterol gallstone disease. The malabsorption of bile acids resulting from ileal disease or resection needs further careful correlation with biliary lipid studies to determine its potential lithogenicity; this experience can then be used in prediction and possible prevention of gallstone disease in hyperlipidemic patients treated with cholestyramine or ileal bypass. Investigations of the lithogenic effects of clofibrate and of oral contraceptive hormones have to be augmented by studies of liver enzymes involved in bile acid biosynthesis and by isotope kinetic estimations of pools, turnover, absorption and secretion rates of bile acids; however, utilization of the full power of the kinetic approach demands precise definition of the biologic behavior of the administered tracers in various physiologic and abnormal states. These biochemical and clinical studies will prove useful in developing measures for prevention of cholesterol gallstones which may result from long-term hormonal contraception, pregnancy, or from use of hypolipidemic drugs.